title: Yondelis® (ET-743, Trabectedin) sensitizes cancer cell lines to CD95-mediated cell death: new molecular insight into the mechanism of action.
abstract: Trabectedin, a naturally occurring substance isolated from the Caribbean marine invertebrate Ecteinascidia turbinata, is the active compound of the antitumor drug Yondelis®. The mechanism of action of Trabectedin has been attributed to interactions with the minor groove of the DNA double helix, thereby affecting transcription of different genes involved in DNA repair and thus facilitating lethal DNA strand breaks. Nevertheless, the existence of other clinically important molecular mechanisms has not yet been fully explored. In this paper we demonstrate how Yondelis®, apart from activating the caspase-8-dependent cascade of apoptosis, sensitizes cancer cells to Fas-mediated cell death at achievable concentrations similar to those found in the plasma of patients. In addition we show that the facilitated apoptosis activated through the Fas death receptor, is associated with a significant increase of membrane Fas/FasL, as well as the modulation of accessory proteins regulating this route, such as FLIP (L) or Akt. Thus, our results propose that the sensitization of the death receptor pathway is an essential mechanism amplifying the cytotoxic properties of Yondelis® that could explain the hepatotoxicity observed in patients treated with this drug. Finally, we also show how the use of dexamethasone as a prophylactic agent that protects against hepatotoxicity induced by Yondelis® may also inhibit some of the cytotoxic properties described in this work. The study of this important mechanism of action should set up the basis for reassessing clinical therapy with Yondelis® in order to improve antitumor treatment outcome.
authors.affiliation: Department of Hematology, University Hospital of Son Dureta, c/Andrea Doria, n° 55, Palma de Mallorca, Spain. jorgej.martinez@ssib.es
authors.forename: Jordi
authors.initials: J
authors.lastname: Martínez-Serra
authors.forename: Elena
authors.initials: E
authors.lastname: Maffiotte
authors.forename: Javier
authors.initials: J
authors.lastname: Martín
authors.forename: Teresa
authors.initials: T
authors.lastname: Bex
authors.forename: María
authors.initials: M
authors.lastname: Navarro-Palou
authors.forename: Teresa
authors.initials: T
authors.lastname: Ros
authors.forename: Joana M
authors.initials: JM
authors.lastname: Plazas
authors.forename: Oliver
authors.initials: O
authors.lastname: Vögler
authors.forename: Antonio
authors.initials: A
authors.lastname: Gutiérrez
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Amat
authors.forename: Rafael
authors.initials: R
authors.lastname: Ramos
authors.forename: Carlos
authors.initials: C
authors.lastname: Saus
authors.forename: Jordi
authors.initials: J
authors.lastname: Ginés
authors.forename: Regina
authors.initials: R
authors.lastname: Alemany
authors.forename: Matias
authors.initials: M
authors.lastname: Diaz
authors.forename: Joan
authors.initials: J
authors.lastname: Besalduch
mesh_terms: D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D004149:Dioxoles / Q000009:adverse effects / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D053222:Fas Ligand Protein / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects; D047492:Peroxisome Proliferator-Activated Receptors / Q000737:chemistry / Q000378:metabolism; D044005:Tetrahydroisoquinolines / Q000009:adverse effects / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000077606:Trabectedin; D019014:fas Receptor / Q000276:immunology / Q000378:metabolism*
chemical_list: D000906:Antibodies; D000970:Antineoplastic Agents; D004149:Dioxoles; D053222:Fas Ligand Protein; D047492:Peroxisome Proliferator-Activated Receptors; D044005:Tetrahydroisoquinolines; D019014:fas Receptor; D003907:Dexamethasone; D000077606:Trabectedin